Methods of inhibiting invasion and metastasis of malignant solid tumors

Abstract

A discovery underlying this invention is the concordance between particular cellular signaling mechanisms and cancer cell growth and metastasis. It has now been discovered that certain compounds inhibit the signal transduction required for the maintenance and driving of the malignant process. These compounds are also effective for the in vivo treatment of solid tumors and related disease states. This invention provides a method for the use of these compounds to inhibit the invasion and metastasis of malignant solid tumors in mammals. This invention further provides a method for using related compounds to treat diseases involving aberrant signal transduction pathways. Some of the compounds used in the methods of the present invention are novel and constitute another aspect of this invention.

What is claimed is: 
     
       1. A method of inhibiting the invasion and metastasis of malignant solid tumors in mammals, said method comprising administering to said mammal an anti-proliferative, anti-invasive and anti-metastasis effective amount of a compound selected from the group of formulas consisting of: ##STR12## wherein: p is an integer of from 0 to 4; Ar 1  is a moiety selected from the group consisting of --Ar 2  --X--Ar 3 , trioxaadamantyl, anthracenyl, anthraquinonyl, phenanthryl, and substituted versions thereof;   Ar 2  and Ar 3  are each aromatic moieties independently selected from the group consisting of phenyl, naphthyl, and substituted versions thereof;   X is a linking moiety selected from the group consisting of O, S, SO 2 , CO, CHCN, straight chain alkyl, alkoxy, and alkoxyalkyl; and   Z is a nitrogen-containing heterocyclic moiety joined to the remainder of the formula at a monovalent ring vertex of said heterocyclic moiety, said heterocyclic moiety selected from the group consisting of pyrazinyl, pyrimidinyl, 1,2,3-triazolo-{4,5-d}-pyrimidinyl, and substituted versions thereof, such that when Z is 1,2,3-triazolo-{4,5-d}-pyrimidinyl or substituted versions thereof, Ar 1  is --Ar 2  --X--Ar 3 .   
     
     
       2. A method in accordance with claim 1 wherein said compound is of formula (I). 
     
     
       3. A method in accordance with claim 1 wherein said compound is of formula (I), Ar 1  is --Ar 2  --X--Ar 3 , Ar 2  and Ar 1  are both substituted phenyl, and Z is a nitrogen-containing heterocyclic moiety selected from the group consisting of 1,2,3-triazolo-{4,5-d}-pyrimidinyl and substituted versions thereof. 
     
     
       4. A method in accordance with claim 1 wherein said compound is of formula (I), p is an integer of from 0 to 2, Ar 1  is a moiety selected from the group consisting of trioxaadamantyl, anthracenyl, anthraquinonyl, phenanthryl, and substituted versions thereof, and Z is a nitrogen-containing heterocyclic moiety selected from the group consisting of 1,2,3-triazolo-{4,5-d}-pyrimidinyl and substituted versions thereof. 
     
     
       5. A method in accordance with claim 1 wherein said compound is of formula (III). 
     
     
       6. A method in accordance with claim 1 wherein said compound is of formula (III), Ar 2  and Ar 3  are both substituted phenyl, and Z is a nitrogen-containing heterocyclic moiety selected from the group consisting of 1,2,3-triazolo-{4,5-d}-pyrimidinyl and substituted versions thereof.